TWI725147B - Containing zonisamide percutaneous absorption type patch preparation - Google Patents

Abstract

As zonisamide or its alkali metal salt, there is provided a transdermal absorption type patch preparation containing zonisamide, which is a transdermal absorption type patch preparation containing zonisamide or its alkali metal salt, and the preparation has a high concentration The drug can be kept in a dissolved state and exert sufficient and sustained efficacy. A transdermal absorption patch preparation comprises zonisamide or its alkali metal salt, an adhesive comprising a (meth)acrylic copolymer having a pyrrolidone group, and an adhesive layer comprising N-alkylpyrrolidone. Skin absorption type patch preparation.

Description

Containing zonisamide percutaneous absorption type patch preparation

The present invention relates to a transdermal absorption type patch preparation provided with an adhesive layer containing zonisamide or its alkali metal salt, an adhesive, and a percutaneous absorption enhancer.

Zonisamide (chemical name: 3-sulfasulfonylmethyl-1,2-benzisoxazole or 1,2-benzisoxazole-3-methylsulfonamide) is currently used as a child or The treatment drugs for adult seizures (partial seizures, general seizures, mixed seizures) or Parkinson's disease treatment drugs are widely used in countries all over the world. In Japan, it is sold under the trade name EXCEGRAN (trademark) as a drug for preventing epileptic seizures, and under the trade name TRERIEF (trademark) as a drug for treating Parkinson's disease, and is administered orally.

In recent years, research has been conducted on transdermal absorption patch preparations with zonisamide. Patent Document 1 discloses a transdermal absorption type patch preparation containing zonisamide that contains absorption enhancers such as lactic acid, α-oligoisostearyl glyceryl ether, and polycinnamyl alcohol. In addition, Patent Document 2 discloses a transdermal absorption type patch preparation containing zonisamide containing a specific ether additive.

【Prior Technical Literature】 【Patent Literature】

Patent Document 1: International Patent Publication No. 2012/105625

Patent Document 2: International Patent No. 2014/021393

Generally speaking, transdermal absorption patch preparations have the advantages of sustainably maintaining the concentration of the drug in the blood, or can be administered to patients with dysphagia, and are better than oral preparations. However, since the transdermal absorption type patch preparation must overcome the barrier of the skin to administer the drug, it is difficult to deliver an effective amount to the body depending on the type of drug. In addition, in order to provide high transdermal absorbability, it is necessary to include a large amount of the drug in a dissolved state in the preparation. However, depending on the basic ingredients such as absorption enhancers and adhesives, it is difficult to maintain stability due to the precipitation of drug crystals in the adhesive during the storage of the preparation. On the other hand, it is desired to weaken the barrier function of the skin, and if an absorption enhancer is added to the preparation, side effects such as skin irritation are often caused.

The above-mentioned Patent Document 1 and Patent Document 2 describe that although the transdermal absorption patch preparation has certain transdermal absorbability, it is still desired to further improve the safety and transdermal absorbability of the transdermal absorption patch preparation.

The object of the present invention is to provide a transdermal absorption type patch preparation containing zonisamide, which is a transdermal absorption type patch preparation containing zonisamide or its alkali metal salt, and the high concentration of the drug in the preparation can be maintained in a dissolved state , In order to play a full and sustained effect. In addition, the object of the present invention is to provide a highly safe transdermal absorption patch preparation containing zonisamide, which has low skin irritation even after long-term administration.

As a result of extensive research conducted by the present inventors, it was found that by using a (meth)acrylic copolymer having a pyrrolidone group as an adhesive (hereinafter It is called (meth)acrylic copolymer containing pyrrolidone group) and N-alkylpyrrolidone as a transdermal absorption enhancer is used in combination to maintain a high concentration of zonisamide in the dissolved state for a long time. Achieve sufficient and continuous transdermal absorbability to complete the present invention.

In addition, by containing a carboxyl-containing (meth)acrylic copolymer (hereinafter referred to as a carboxyl-containing (meth)acrylic copolymer) in the above-mentioned adhesive, the drug will not decrease over a long period of time. Permeability, skin irritation is suppressed, and high safety is achieved.

That is, the present invention is as follows.

[Item 1] A transdermal absorption type patch preparation, comprising a transdermal absorption type patch preparation containing an adhesive layer having the following ingredients: zonisamide or an alkali metal salt thereof, containing (methyl) having a pyrrolidone group ) Adhesives for acrylic copolymers, and percutaneous absorption enhancers containing N-alkylpyrrolidone.

[Item 2] The percutaneously absorbable patch preparation as described in Item 1, wherein the N-alkylpyrrolidone is N-laurylpyrrolidone, N-octylpyrrolidone, N-heptylpyrrolidone, N-hexylpyrrolidone, N-nonylpyrrolidone, N-decylpyrrolidone, N-undecylpyrrolidone, N-tridecylpyrrolidone, N-tetradecylpyrrolidone, N-pentadecylpyrrolidone, N-hexadecyl Pyrrolidone, N-heptadecylpyrrolidone or N-octadecylpyrrolidone.

[Item 3] The percutaneously absorbable patch preparation described in Item 2, wherein the N-alkylpyrrolidone is N-laurylpyrrolidone or N-octylpyrrolidone.

[Item 4] The transdermal absorption type patch preparation as described in Item 3, The aforementioned N-alkylpyrrolidone is N-laurylpyrrolidone.

[Item 5] The percutaneously absorbable patch preparation described in any one of items 1 to 4, wherein the adhesive is a (meth)acrylic copolymer having a pyrrolidone group and a (meth)acrylic acid copolymer having a carboxyl group Acrylic copolymer.

[Item 6] The transdermal absorption type patch preparation described in any one of Items 1 to 5, wherein the above-mentioned transdermal absorption enhancer contains N-laurylpyrrolidone, and alternatively polyethylene glycol monolaurate, At least one of the group consisting of polycinnamyl alcohol, isopropyl myristate, isopropyl palmitate, oleyl oleate, and hexyl laurate.

[Item 7] The transdermal absorption type patch preparation as described in Item 6, wherein the above-mentioned transdermal absorption enhancer contains N-laurylpyrrolidone, selected from polyethylene glycol monolaurate and isopropyl myristate At least one of the group consisting of esters.

[Item 8] The transdermal absorption type patch preparation described in Item 7, wherein the transdermal absorption enhancer contains N-laurylpyrrolidone and isopropyl myristate.

[Item 9] The transdermal absorption patch preparation described in any one of items 1 to 8, wherein the (meth)acrylic copolymer having a pyrrolidone group is 2-ethylhexyl acrylate·vinylpyrrolidone copolymer Combination, hydroxyethyl acrylate‧vinylpyrrolidone copolymer, butyl acrylate‧vinylpyrrolidone copolymer, cyclohexyl acrylate‧vinylpyrrolidone copolymer, 2-ethylhexyl methacrylate‧vinylpyrrolidone copolymer, methyl Cyclohexyl acrylate‧vinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧methylvinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧hydroxyethyl acrylate‧vinylpyrrolidine Ketone copolymer, 2-ethylhexyl acrylate‧acrylic acid‧vinylpyrrolidone copolymer, butyl acrylate‧acrylic acid‧vinylpyrrolidone copolymer, or 2-ethylhexyl acrylate‧acrylic acid‧methyl vinylpyrrolidone copolymer.

[Item 10] The transdermal absorption patch preparation as described in Item 9, wherein the (meth)acrylic copolymer containing pyrrolidone group is 2-ethylhexyl acrylate·vinylpyrrolidone copolymer, hydroxyethyl acrylate Ester‧vinylpyrrolidone copolymer, butyl acrylate‧vinylpyrrolidone copolymer, 2-ethylhexylmethacrylate‧vinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧methylvinylpyrrolidone copolymer, acrylic acid 2 -Ethylhexyl‧Hydroxyethyl acrylate‧Vinylpyrrolidone copolymer, or 2-ethylhexyl acrylate‧Acrylic acid‧Vinylpyrrolidone copolymer.

[Item 11] The percutaneously absorbable patch preparation described in Item 10, wherein the (meth)acrylic copolymer containing a pyrrolidone group is 2-ethylhexyl acrylate·vinylpyrrolidone copolymer.

[Item 12] The percutaneously absorbable patch preparation described in any one of Items 5 to 11, wherein the (meth)acrylic copolymer containing carboxyl groups is acrylic acid‧octyl acrylate copolymer and 2-ethyl acrylate Acrylic acid copolymer, 2-ethylhexyl acrylate, methyl acrylate, acrylic acid, glycidyl methacrylate copolymer, 2-ethylhexyl acrylate, acrylic acid, vinylpyrrolidone copolymer, acrylic acid 2-ethylhexyl‧acrylic acid‧methylvinylpyrrolidone copolymer, butyl acrylate‧acrylic acid‧vinylpyrrolidone copolymer, acrylic acid‧butyl acrylate copolymer, acrylic acid‧hydroxyethyl acrylate copolymer, or 2-ethyl acrylate Hexyl ‧ Vinyl Acetate ‧ Butyl Acrylate ‧ Acrylic Copolymer.

[Item 13] The transdermal absorption patch preparation described in any one of items 5 to 11, wherein the (meth)acrylic copolymer containing carboxyl groups is acrylic acid‧octyl acrylate copolymer, 2-ethyl acrylate Acrylic acid ‧ vinyl acetate ‧ acrylic copolymer, 2-ethylhexyl acrylate ‧ methyl acrylate ‧ acrylic acid ‧ methyl glycidyl ester copolymer, acrylic acid ‧ butyl acrylate copolymer, acrylic acid ‧ hydroxyethyl acrylate copolymer, Or 2-ethylhexyl acrylate‧vinyl acetate‧butyl acrylate‧acrylic acid copolymer.

[Item 14] The transdermal absorption patch preparation described in Item 12, wherein the above-mentioned carboxyl-containing (meth)acrylic copolymer is acrylic acid‧octyl acrylate copolymer or 2-ethylhexyl acrylate‧acetic acid Vinyl ester ‧ acrylic copolymer.

[Item 15] The percutaneously absorbable patch preparation described in Item 14, wherein the (meth)acrylic copolymer containing a carboxyl group is acrylic acid and octyl acrylate copolymer.

[Item 16] The transdermal absorption patch preparation as described in any one of Items 1 to 15, wherein the content of the zonisamide or its alkali metal salt in the transdermal absorption patch preparation is based on In terms of zonisamide, it is 1% by mass to 20% by mass relative to the total amount of the adhesive layer.

[Item 17] The transdermal absorption patch preparation as described in Item 16, wherein the content of the zonisamide or its alkali metal salt in the transdermal absorption patch preparation is calculated as zonisamide , Relative to the total amount of the adhesive layer, 3% by mass to 10% by mass.

[Item 18] The transdermal absorption patch preparation as described in any one of items 1 to 15, the content of the adhesive in the transdermal absorption patch preparation The amount is 30% by mass to 98% by mass relative to the total amount of the above-mentioned adhesive layer.

[Item 19] The transdermal absorption patch preparation described in any one of items 1 to 15, 17 or 18, wherein the content of the adhesive in the transdermal absorption patch preparation is relative to the adhesive The total amount of the agent layer is 60% to 85% by mass.

[Item 20] The transdermal absorption patch preparation described in any one of items 1 to 15 or 17 to 19, wherein the (meth)acrylic acid having a pyrrolidone group in the transdermal absorption patch preparation The content of the copolymer-like substance is 50% by mass to 85% by mass relative to the total amount of the adhesive layer.

[Item 21] The transdermal absorption patch preparation described in any one of Items 1 to 19, wherein the (meth)acrylic copolymer having a pyrrolidone group in the transdermal absorption patch preparation The content is 50% by mass to 70% by mass relative to the total amount of the adhesive layer.

[Item 22] The percutaneously absorbable patch preparation described in any one of items 1 to 17 or 21, wherein the (meth)acrylic copolymer having a carboxyl group in the percutaneously absorbable patch preparation The content of, relative to the total amount of the adhesive layer, is 1% by mass to 20% by mass.

[Item 23] The transdermal absorption type patch preparation described in any one of items 1 to 17 or 19 to 22, wherein the above-mentioned (meth)acrylic group having a carboxyl group in the transdermal absorption type patch preparation The content of the copolymer is 5 to 15% by mass relative to the total amount of the adhesive layer.

[Item 24] The transdermal absorption patch preparation described in any one of items 1 to 17, 22, or 23, wherein the content of the transdermal absorption enhancer in the transdermal absorption patch preparation is relative to The total amount of the adhesive layer is 1% by mass to 40% by mass.

[Item 25] The transdermal absorption patch preparation described in any one of items 1 to 17 or 22 to 24, wherein the content of the transdermal absorption enhancer in the transdermal absorption patch preparation is relative to The total amount of the adhesive layer is 25% to 35% by mass.

[Item 26] The transdermal absorption patch preparation as described in any one of items 1 to 17 or 21 to 25, wherein the content of the N-alkylpyrrolidone in the transdermal absorption patch preparation is relative to The total amount of the adhesive layer is 1% by mass to 30% by mass.

[Item 27] The transdermal absorption patch preparation described in any one of items 1 to 17 or 21 to 26, wherein the content of the N-alkylpyrrolidone in the transdermal absorption patch preparation is relative to The total amount of the adhesive layer is 13% by mass to 20% by mass.

[Item 28] The percutaneously absorbable patch preparation according to any one of items 1 to 27, wherein the compounding amount of the adhesive in the percutaneously absorbable patch preparation is relative to the above-mentioned zonisamide 1 part by mass of its alkali metal salt is 1.5 parts by mass to 40 parts by mass.

[Item 29] The percutaneously absorbable patch preparation as described in Item 28, wherein the compounding amount of the adhesive in the percutaneously absorbable patch preparation is relative to the above-mentioned zonisamide or its alkali metal salt 1 quality department is 10 to 25 quality department.

[Item 30] The transdermal absorption patch preparation described in any one of items 1 to 29, wherein the blending amount of the transdermal absorption enhancer in the transdermal absorption patch preparation is relative to the azole Nisamide or its alkali metal salt 1 part by mass is 0.05 to 40 parts by mass.

[Item 31] The transdermal absorption patch preparation described in any one of Items 1 to 30, wherein the blending amount of the transdermal absorption enhancer in the transdermal absorption patch preparation is relative to the azole 1 part by mass of nisamide or its alkali metal salt is 0.1 to 30 parts by mass.

[Item 32] The transdermal absorption patch preparation according to any one of Item 31, wherein the blending amount of the transdermal absorption enhancer in the transdermal absorption patch preparation is relative to the zonisa 1 part by mass of amine or its alkali metal salt is 1 part by mass to 10 parts by mass.

[Item 33] The transdermal absorption patch preparation according to Item 1, wherein the adhesive includes a (meth)acrylic copolymer having a pyrrolidone group, and the transdermal absorption enhancer includes N-laurylpyrrolidone, With respect to 1 part by mass of the zonisamide or its alkali metal salt, the compounding amount of the adhesive is 1.5 parts by mass to 40 parts by mass, and the compounding amount of the transdermal absorption enhancer is 1 part by mass to 30 parts by mass.

[Item 34] The transdermal absorption patch preparation according to any one of Item 1, wherein the adhesive includes 2-ethylhexyl acrylate·vinylpyrrolidone copolymer, and the transdermal absorption enhancer includes N-laurel Based on 1 part by mass of the above-mentioned zonisamide or its alkali metal salt, the compounding amount of the adhesive is 5 parts by mass to 30 parts by mass, and the compounding amount of the transdermal absorption enhancer is 1 part by mass to 20 parts by mass relative to 1 part by mass of the above-mentioned zonisamide or its alkali metal salt. unit.

[Item 35] The transdermal absorption patch preparation as described in Item 1, wherein the adhesive contains 2-ethylhexyl acrylate and vinylpyrrolidone copolymerization The transdermal absorption enhancer includes N-laurylpyrrolidone and isopropyl myristate, and the blending amount of the adhesive is 10 parts by mass to 30 parts by mass relative to 1 part by mass of the zonisamide or its alkali metal salt. In the mass part, the blending amount of the above-mentioned transdermal absorption enhancer is 1 mass part to 15 mass parts.

[Item 36] The transdermal absorption patch preparation described in Item 1, wherein the adhesive includes 2-ethylhexyl acrylate·vinylpyrrolidone copolymer and acrylic·octyl acrylate copolymer, and the above-mentioned transdermal absorption promotes The agent contains N-laurylpyrrolidone and isopropyl myristate, and the compounding amount of the adhesive is 10 parts by mass to 25 parts by mass relative to 1 part by mass of the above-mentioned zonisamide or its alkali metal salt, and the above-mentioned transdermal absorption The blending amount of the accelerator is 1 part by mass to 10 parts by mass.

[Item 37] The transdermal absorption patch preparation described in Item 1, wherein the adhesive includes 2-ethylhexyl acrylate·vinylpyrrolidone copolymer and acrylic·octyl acrylate copolymer, and the above-mentioned transdermal absorption promotes The agent contains N-laurylpyrrolidone and isopropyl myristate, and the blending amount of the acrylic acid 2-ethylhexyl‧vinylpyrrolidone copolymer is 10 parts by mass relative to 1 part by mass of the zonisamide or its alkali metal salt. Part ~ 20 parts by mass, the blending amount of the acrylic acid and octyl acrylate copolymer is 1 to 3 parts by mass, the blending amount of the N-laurylpyrrolidone is 1 to 5 parts by mass, and the above isopropyl myristate The blending amount of the ester is 1 part by mass to 5 parts by mass.

[Item 38] The percutaneously absorbable patch preparation described in any one of items 1 to 37, the adhesive layer (including zonisamide or its alkali metal salt, percutaneous absorption The thickness of the layer of accelerating agent, adhesive, and other additives as needed is 30μm~200μm.

The present invention contains zonisamide percutaneous absorption type patch preparation, which is composed of a combination of a specific adhesive and a specific percutaneous absorption enhancer, and can safely and for a long time exert good transdermal absorbability.

Hereinafter, suitable implementation aspects of the present invention will be described in detail.

1. Zonisamide or its alkali metal salt

In the present invention, zonisamide (chemical name: 3-sulfasulfonylmethyl-1,2-benzisoxazole or 1,2-benzisoxazole-3-methylsulfonamide) or Its metal salt. Preferably, zonisamide can be cited.

As the metal salt of zonisamide, sodium salt, potassium salt, and lithium salt can be cited. Preferably, sodium salt and potassium salt can be cited. More preferably, sodium salt can be cited. Zonisamide can be produced according to the methods described in Japanese Patent Publication No. 60-33114, Japanese Patent Publication No. 61-59288, and US Patent No. 4,172,896, for example.

Zonisamide or its alkali metal salt may have polymorphs, and the zonisamide in the present invention includes all crystal forms.

Since zonisamide of the present invention also exists in the form of one or both of hydrates and solvates, the present invention also includes one or both of hydrates or solvates of zonisamide or its alkali metal salt. By.

The so-called dissolution of the drug of the present invention means a state in which a part of the drug is dissolved in addition to the state in which all the drug in the preparation is dissolved.

The content of zonisamide or its alkali metal salt in the transdermal absorption patch preparation of the present invention (in the case of zonisamide alkali metal, the value when converted to zonisamide) is based on the total amount of the adhesive layer The mass% occupied at 100 mass% is not particularly limited as long as it can be formulated. The content of zonisamide or its alkali metals in the transdermal patch preparation is preferably 1% by mass to 20% by mass. More preferably, 3% by mass to 20% by mass can be cited. More preferably, 3% by mass to 15% by mass can be cited. Most preferably, 3% by mass to 10% by mass can be cited.

The lower limit of the content of zonisamide or its alkali metal salt in the transdermal patch preparation is preferably 1% by mass or more. More preferably, it is 3% by mass or more.

The upper limit of the content of zonisamide or its alkali metal salts in the percutaneously absorbable patch preparation can be enumerated, preferably 20% by mass or less, more preferably 15% by mass or less, and still more preferably 10% by mass or less , And more preferably 6 mass% or less.

In addition, when the content of zonisamide or its alkali metal salt is less than 1% by mass, a sustained transdermal absorption effect cannot be obtained. On the other hand, when the content of zonisamide or its alkali metal salt exceeds 20% by mass or more, the solubility of the drug may be insufficient.

2. Adhesive

The adhesive, which is the base component of the percutaneously absorbable patch preparation of the present invention, contains a (meth)acrylic copolymer having a pyrrolidone group. Since zonisamide is a poorly soluble drug, when the adhesive does not have a pyrrolidone group, sufficient solubility of the drug cannot be obtained. By using (meth)acrylic copolymers containing pyrrolidone groups Combined, it can increase the solubility of zonisamide for adhesives.

The content of the adhesive in the percutaneously absorbable patch preparation of the present invention is preferably 30 to 98% by mass when the total amount of the adhesive layer is taken as 100% by mass. More preferably, 40% by mass to 95% by mass can be cited. More preferably, 50% by mass to 90% by mass can be cited. Most preferably, 60% by mass to 85% by mass can be cited.

The compounding amount of the adhesive in the percutaneously absorbable patch preparation of the present invention is preferably a ratio of 1.5 parts by mass to 4 parts by mass relative to 1 part by mass of zonisamide or its alkali metal salt. More preferably, the ratio of 5 mass parts to 30 mass parts can be cited. More preferably, the ratio of 10 mass parts to 30 mass parts can be cited. Most preferably, the ratio of 10 mass parts to 25 mass parts can be cited.

The pyrrolidone group-containing (meth)acrylic copolymer of the present invention is not particularly limited as long as it has a pyrrolidone group. The (meth)acrylic copolymer having a pyrrolidone group includes at least one (meth)acrylate monomer and at least one monomer having a pyrrolidone group (hereinafter referred to as a pyrrolidone group-containing monomer). The case of the body) of the copolymer.

In addition, the (meth)acrylic copolymer containing a pyrrolidone group may also have a carboxyl group.

As said (meth)acrylate type monomer, acrylic acid, methacrylic acid, or its derivative(s) can be mentioned. These substances can be used individually or in combination of two or more kinds. Examples of the above-mentioned derivatives include acrylic acid esters and methacrylic acid esters.

Specific examples of acrylates are preferably n-butyl acrylate, n-hexyl acrylate, n-octyl acrylate, 2-ethylhexyl acrylate, propylene Isooctyl acrylate, isononyl acrylate, n-decyl acrylate, isodecyl acrylate, hydroxyethyl acrylate, cyclohexyl acrylate.

Specific examples of methacrylates are preferably -n-decyl methacrylate, dodecyl methacrylate, 2-ethylhexyl methacrylate, isodecyl methacrylate, lauryl methacrylate, Cyclohexyl methacrylate.

In addition, (meth)acrylate can be used individually or in combination of 2 or more types, respectively.

As specific examples of the above-mentioned pyrrolidone group-containing monomer, preferably, vinylpyrrolidone or methylvinylpyrrolidone can be cited. More preferably, N-vinyl-2-pyrrolidone can be mentioned.

In addition, the pyrrolidone group-containing monomers can be used alone or in combination of two or more kinds.

Specific examples of the (meth)acrylic copolymer having a pyrrolidone group preferably include 2-ethylhexyl acrylate·vinylpyrrolidone copolymer, hydroxyethyl acrylate·vinylpyrrolidone copolymer, and butyl acrylate Ester‧Vinylpyrrolidone copolymer, acrylic cyclohexyl‧vinylpyrrolidone copolymer, 2-ethylhexyl methacrylate‧vinylpyrrolidone copolymer, cyclohexyl methacrylate‧vinylpyrrolidone copolymer, 2-ethyl acrylate Hexyl‧Methyl Vinylpyrrolidone Copolymer, 2-Ethylhexyl Acrylate‧Hydroxyethyl Acrylate‧Vinylpyrrolidone Copolymer, 2-Ethylhexyl Acrylate‧Acrylic Acid‧Vinylpyrrolidone Copolymer, Butyl Acrylate‧Acrylic Acid‧Ethylene Ylpyrrolidone copolymer, or 2-ethylhexyl acrylate‧acrylic acid‧methylvinylpyrrolidone copolymer.

As a (meth)acrylic copolymer with pyrrolidone group More preferably, specific examples include 2-ethylhexyl acrylate‧vinylpyrrolidone copolymer, hydroxyethyl acrylate‧vinylpyrrolidone copolymer, butyl acrylate‧vinylpyrrolidone copolymer, methacrylic acid 2- Ethylhexyl‧vinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧methylvinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧hydroxyethyl acrylate‧vinylpyrrolidone copolymer, or 2-ethylhexyl acrylate ‧Acrylic acid‧Vinylpyrrolidone copolymer.

As a specific example of the (meth)acrylic copolymer which has a pyrrolidone group, a 2-ethylhexyl acrylate·vinylpyrrolidone copolymer is more preferable.

As the adhesive of the pyrrolidone group-containing (meth)acrylic copolymer used in the present invention, commercially available products can be used. Specifically, for example, acrylic adhesives such as MAS683 manufactured by CosMED.

The content of the pyrrolidone group-containing (meth)acrylic copolymer in the transdermal absorption patch preparation of the present invention (the content of the individual component when contained alone, and the total amount of these components when two or more types of components are contained) Preferably, when the total amount of the adhesive layer is taken as 100% by mass, 30% by mass to 98% by mass can be cited. More preferably, 40% by mass to 95% by mass can be cited. More preferably, 50% by mass to 90% by mass can be cited. Still more preferably, 50% by mass to 85% by mass can be cited. Most preferably, 50% by mass to 70% by mass can be cited.

The lower limit of the content of the pyrrolidone group-containing (meth)acrylic copolymer in the percutaneously absorbable patch preparation is preferably 30 mass or more. More preferably, it is 40% by mass or more. More preferably, it is 50% by mass or more.

Pyrrolidone-containing (meth)propane in transdermal patch preparations The upper limit of the content of the olefinic acid copolymer is preferably 98% by mass or less. More preferably, it is 95% by mass or less. More preferably, it is 90% by mass or less. Still more preferably, it is 85% by mass or less. Most preferably, it is 70% by mass or less.

In addition, if the content of the pyrrolidone group-containing (meth)acrylic copolymer is less than 30% by mass, the cohesive force of the adhesive layer will be insufficient, resulting in the problem of residual adhesive on the skin, or low solubility of the drug, resulting in crystallization Problems such as precipitation. On the other hand, if the content of the pyrrolidone group-containing (meth)acrylic copolymer exceeds 98% by mass, the drug concentration becomes low, and the release of the drug from the preparation becomes low, making it impossible to obtain sufficient drug delivery. Skin absorbability.

In the transdermal absorption patch preparation of the present invention, the compounding amount of the pyrrolidone group-containing (meth)acrylic copolymer of the adhesive (when contained alone, this is the content of the single component, when two or more types of components are contained) It is the total amount of these components), Preferably it is a ratio of 1.5 mass parts-40 mass parts with respect to 1 mass part of zonisamide or its alkali metal salt. More preferably, the ratio of 5 mass parts to 30 mass parts can be cited. More preferably, the ratio of 10 mass parts to 30 mass parts can be cited. Most preferably, the ratio of 10 mass parts to 20 mass parts can be cited.

The adhesive used in the present invention preferably includes (meth)acrylic copolymers containing carboxyl groups in addition to (meth)acrylic copolymers having pyrrolidone groups. According to the type or amount of transdermal absorber, pay attention to skin irritation. By coexisting with an appropriate amount of carboxyl-containing (meth)acrylic copolymer, it can improve the transdermal absorbability of the drug while suppressing the absorption enhancer Caused by skin irritation. The (meth)acrylic copolymers containing carboxyl groups are not particularly limited as long as they contain carboxyl groups. They can also be used in the copolymerization of acrylic acid. The ingredients have carboxyl groups. Examples of (meth)acrylic copolymers containing carboxyl groups include copolymers of at least two (meth)acrylic monomers, or at least one (meth)acrylic monomer and acetic acid Copolymer of vinyl ester monomers.

As said (meth)acrylic monomer, acrylic acid, methacrylic acid, or its derivative(s) can be mentioned. As specific examples of derivatives, (meth)acrylate monomers can be cited.

Specific examples of acrylates preferably include n-butyl acrylate, n-hexyl acrylate, n-octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate, N-decyl acrylate, isodecyl acrylate, hydroxyethyl acrylate.

As specific examples of methacrylates, preferably, n-decyl methacrylate, dodecyl methacrylate, 2-ethylhexyl methacrylate, isodecyl methacrylate, Lauryl methacrylate, glycidyl methacrylate, etc.

As specific examples of (meth)acrylates, preferably, 2-ethylhexyl acrylate, octyl acrylate, butyl acrylate, cyclohexyl acrylate, octyl methacrylate, 2-ethyl methacrylate can be cited. Hexyl methacrylate, butyl methacrylate, or cyclohexyl methacrylate.

In addition, (meth)acrylate can be used individually or in combination of 2 or more types, respectively.

As specific examples of (meth)acrylic copolymers containing carboxyl groups, preferably, acrylic acid‧octyl acrylate copolymers, 2-ethylhexyl acrylate‧vinyl acetate‧acrylic acid copolymers, acrylic acid 2- Ethylhexyl Ester ‧ Methyl acrylate ‧ Acrylic acid ‧ Methyl glycidyl ester copolymer, 2-ethylhexyl acrylate ‧ Acrylic acid ‧ Vinyl pyrrolidone copolymer, 2-ethylhexyl acrylate ‧ Acrylic acid ‧ Methyl vinyl pyrrolidone copolymer, Butyl acrylate Ester‧Acrylic acid‧Vinylpyrrolidone copolymer, acrylic acid‧butyl acrylate copolymer, acrylic acid‧hydroxyethyl acrylate copolymer, or 2-ethylhexyl acrylate‧vinyl acetate‧butyl acrylate‧acrylic acid copolymer.

Specific examples of (meth)acrylic copolymers containing carboxyl groups, more preferably, acrylic acid‧octyl acrylate copolymer, 2-ethylhexyl acrylate‧vinyl acetate‧acrylic acid copolymer, 2-ethyl acrylate copolymer Hexyl hexyl ester‧methyl acrylate‧acrylic acid‧methyl glycidyl ester copolymer, acrylic acid‧butyl acrylate copolymer, acrylic acid‧hydroxyethyl acrylate copolymer, or 2-ethylhexyl acrylate‧vinyl acetate‧butyl acrylate ‧Acrylic copolymer.

As a specific example of the (meth)acrylic copolymer containing a carboxyl group, more preferably, acrylic acid‧octyl acrylate copolymer or 2-ethylhexyl acrylate‧vinyl acetate‧acrylic acid copolymer can be cited.

As a specific example of the (meth)acrylic copolymer containing a carboxyl group, it is still more preferable to include acrylic acid·octyl acrylate copolymer.

In addition, those classified into two (meth)acrylic copolymers containing pyrrolidone groups and (meth)acrylic copolymers containing carboxyl groups can be used as (meth)acrylic copolymers containing pyrrolidone groups, It can also be used as a (meth)acrylic copolymer containing carboxyl groups.

The adhesive of the (meth)acrylic copolymer containing a carboxyl group used in the present invention may be a commercially available product. As a specific example of the (meth)acrylic copolymer containing a carboxyl group, Duro-Tak manufactured by Henkel 87-200A, Duro-Tak 87-2194, Duro-Tak 87-2353, Duro-Tak 87-2051 or Duro-Tak 87-235A, etc.

The content of the carboxyl group-containing (meth)acrylic copolymer in the transdermal absorption patch preparation of the present invention (when contained alone, this is the content of the individual component, and when two or more types of components are contained, it is the total amount of these components ) Preferably, when the total amount of the adhesive layer is 100% by mass, 20% by mass or less can be cited. More preferably, 1% by mass to 20% by mass can be cited. More preferably, 5 to 20% by mass can be cited. Still more preferably, 5 to 15% by mass can be cited.

The lower limit of the content of the carboxyl group-containing (meth)acrylic copolymer in the percutaneously absorbable patch preparation is preferably 1% by mass or more. More preferably, it can be 5% by mass or more.

The upper limit of the content of the (meth)acrylic copolymer containing a carboxyl group in the percutaneously absorbable patch preparation is preferably 20% by mass or less. More preferably, it is 15% by mass or less.

In addition, if the content of the carboxyl group-containing (meth)acrylic copolymer is less than 1% by mass, the skin irritation inhibitory effect of the absorption enhancer will be reduced. On the other hand, if the content of the carboxyl group-containing (meth)acrylic copolymer exceeds 20% by mass, the content of the pyrrolidone group-containing (meth)acrylic copolymer will relatively decrease, and the solubility of the drug will decrease, resulting in crystal precipitation, etc. Bad effect.

In the transdermal absorption patch preparation of the present invention, the compounding amount of the carboxyl group-containing (meth)acrylic copolymer of the adhesive (when contained alone, this is the content of the individual component, and when two or more types of components are contained, it is The sum of these ingredients Amount) is preferably a ratio of 20 parts by mass or less with respect to 1 part by mass of zonisamide or its alkali metal salt. More preferably, a ratio of 10 parts by mass or less can be cited. More preferably, the ratio of 0.05 mass parts to 5 mass parts can be cited. Most preferably, the ratio of 1 mass part to 3 mass parts can be cited.

3. Transdermal absorption enhancer

The percutaneous absorption type patch preparation of the present invention contains N-alkylpyrrolidone as a percutaneous absorption enhancer. By using N-alkylpyrrolidone, sufficient and sustained drug absorption through the skin can be achieved.

The "alkane" of N-alkylpyrrolidone means "alkyl" and means a linear or branched saturated hydrocarbon group. For example, "C _1-30 alkyl group" is an alkyl group having 1 to 30 carbon atoms. The same is true for other numbers. The "alkane" of N-alkylpyrrolidone is preferably, and a "C _1-25 alkyl group" is exemplified. More preferably, "C _3-20 alkyl group" can be mentioned. Even more preferably, "C _5-15 alkyl" can be mentioned. Most preferably, "C _6-15 alkyl group" can be mentioned.

Preferable specific examples of N-alkylpyrrolidone include N-laurylpyrrolidone, N-octylpyrrolidone, N-heptylpyrrolidone, N-hexylpyrrolidone, N-nonylpyrrolidone, and N-decylpyrrolidone. , N-undecylpyrrolidone, N-tridecylpyrrolidone, N-tetradecylpyrrolidone, N-pentadecylpyrrolidone, N-hexadecylpyrrolidone, N-heptadecylpyrrolidone, or N-octadecylpyrrolidone. More preferably, N-laurylpyrrolidone or N-octylpyrrolidone may be mentioned. Even more preferably, N-laurylpyrrolidone can be cited.

In the percutaneous absorption type patch preparation of the present invention, when the total amount of the adhesive layer is taken as 100% by mass, the percutaneous absorption enhancer in the percutaneous patch preparation of the present invention is preferably, 1% by mass to 40% by mass. More preferably, it may be 5% to 40% by mass. More preferably, 15% by mass to 35% by mass can be cited. Most preferably, 25% by mass to 35% by mass can be cited.

The blending amount of the transdermal absorption enhancer in the transdermal absorption patch preparation of the present invention is preferably such that, relative to 1 part by mass of zonisamide or its alkali metal salt, it may be 0.05 to 40 parts by mass. proportion. More preferably, the ratio of 0.1 mass part to 30 mass part can be mentioned. More preferably, a ratio of 0.5 mass parts to 30 mass parts can be cited. Even more preferably, the ratio of 1 mass part to 30 mass parts can be cited. More preferably, the ratio of 1 mass part to 20 mass parts is mentioned. Still more preferably, the ratio of 1 mass part to 15 mass parts can be cited. Most preferably, the ratio of 1 mass part to 10 mass parts can be cited.

The content of N-alkylpyrrolidone in the percutaneously absorbable patch preparation of the present invention (the content of a single component when contained alone, and the total amount of these components when two or more kinds of components are contained) is preferably, When the total amount of the adhesive layer is 100% by mass, 1% by mass to 30% by mass can be cited. More preferably, it may be 5% to 30% by mass. More preferably, 13% by mass to 25% by mass can be cited. Most preferably, 13% by mass to 20% by mass can be cited.

The lower limit of the N-alkylpyrrolidone in the percutaneously absorbable patch preparation is preferably 1% by mass or more. More preferably, it can be 5% by mass or more. More preferably, it is 13% by mass or more.

The upper limit of the N-alkylpyrrolidone in the percutaneously absorbable patch preparation is preferably 30% by mass or less. More preferably, it is 25% by mass or less. More preferably, it is 20% by mass or less.

In addition, if the content of N-alkylpyrrolidone is less than 1% by mass, Sufficient transdermal absorbability of the drug cannot be obtained. In addition, if the N-alkylpyrrolidone content exceeds 30% by mass, skin irritation problems such as redness and swelling may occur.

The blending amount of N-alkylpyrrolidone as the percutaneous absorption enhancer in the transdermal absorption patch preparation of the present invention (when contained alone, this is the content of a single ingredient, and when two or more types of ingredients are contained, these ingredients are used The total amount of) is preferably a ratio of 1 part by mass to 30 parts by mass relative to 1 part by mass of zonisamide or its alkali metal salt. More preferably, a ratio of 1 mass part to 20 mass parts can be exemplified. More preferably, the ratio of 1 mass part to 10 mass parts can be exemplified. Preferably, a ratio of 1 mass part to 5 mass parts can be exemplified.

The percutaneously absorbable patch preparation used in the present invention may further contain an absorption enhancer other than N-alkylpyrrolidone (hereinafter, it may be referred to as another absorption enhancer). Specific examples of other absorption enhancers are preferably selected from polyethylene glycol monolaurate, polycinnamyl alcohol, isopropyl myristate, isopropyl palmitate, oleyl oleate, Hexyl laurate, diethyl sebacate, diisopropyl adipate, propylene glycol, dipropylene glycol, POE hydrogenated castor oil, sorbitan monooleate, sorbitan monolaurate, POE stearyl alcohol At least one of the group consisting of ether and monostearate PEG. More preferably, it can be selected from the group consisting of polyethylene glycol monolaurate, polycinnamyl alcohol, isopropyl myristate, isopropyl palmitate, oleyl oleate, and hexyl laurate. At least one of them. More preferably, it is selected from at least one of the group consisting of polyethylene glycol monolaurate and isopropyl myristate. Most preferably, isopropyl myristate can be cited.

Other absorption promotion in the percutaneous absorption patch preparation of the present invention The content of the agent (the content of the individual components when contained alone, and the total amount of these components when two or more components are contained), when the total amount of the adhesive layer is 100% by mass, it is preferably, including 1% by mass to 30% by mass. More preferably, it may be 5% to 30% by mass. More preferably, 10% by mass to 30% by mass can be cited. Most preferably, 10% by mass to 20% by mass can be cited.

The lower limit of the content of the other absorption enhancer in the transdermal patch preparation is preferably 1% by mass or more. More preferably, it can be 5% by mass or more. More preferably, it may be 10% by mass or more.

The upper limit of the content of the other absorption enhancer in the percutaneously absorbable patch preparation is preferably 30% by mass or less. More preferably, it is 20% by mass or less.

In addition, if the content of other absorption enhancers is less than 1% by mass, sufficient transdermal absorbability of the drug may not be obtained in some cases. On the other hand, if the content of other absorption enhancers exceeds 30% by mass, it may not only cause skin irritation such as redness and swelling, but also deteriorate the physical properties of the preparation. After the preparation is applied, residual glue may occur. phenomenon.

The blending amount of the above-mentioned other absorption enhancers (the content of the individual components when contained alone, and the total amount of these components when two or more types of components are contained) in the transdermal absorption patch preparation of the present invention is preferably: The ratio of 0.1 parts by mass to 20 parts by mass relative to 1 part by mass of zonisamide or its alkali metal salt can be cited. More preferably, the ratio of 1 mass part to 10 mass parts can be cited. Most preferably, the ratio of 1 mass part to 5 mass parts can be cited.

The content of zonisamide or its alkali metal salt, transdermal absorption enhancer, and adhesive, when the following additives are added, should be understood as relative to the addition of The mass% of the entire adhesive layer of the agent (excluding the support and release film).

4. Other

The preparation of the present invention is provided with an adhesive layer containing the above-mentioned zonisamide or its alkali metal salt, a percutaneous absorption enhancer, and an adhesive. In addition to the above, the preparation of the present invention may contain additives commonly used in percutaneously absorbable patch preparations, as needed, within a range that does not impair the effects of the present invention.

For example, the above-mentioned acrylic adhesive is used as an adhesive base. In order to adjust the adhesiveness and stability of the adhesive, it can contain an appropriate amount of softeners such as polyisobutylene, polybutene, liquid paraffin, and water-soluble polyvinylpyrrolidone and polyvinyl alcohol. Polymers, cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, silicon compounds such as anhydrous silicic acid, light anhydrous silicic acid, inorganic fillers such as silica, And antioxidants such as dibutyl hydroxytoluene. In addition, if necessary, it can also contain an appropriate amount of preservatives, cooling agents, bactericides, flavoring agents and coloring agents.

The components of the preparation of the present invention have been described above.

The transdermal absorption patch preparation system of the present invention uses an adhesive composition containing the above-mentioned zonisamide or its alkali metal salt, a percutaneous absorption enhancer, and an adhesive as an adhesive layer, which is laminated on a support, It can be used as a laminate structure in which the adhesive layer is covered with a release liner (liner). In actual use, the release liner can be torn off, and one side of the adhesive layer can be attached to the desired skin.

The support used in the present invention is not particularly limited. It is possible to use a stretchable or non-stretchable substance that is generally used as an adhesive agent. Specific examples of the support are preferably polyethylene terephthalate (hereinafter referred to as PET), polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, Films or sheets made of synthetic resins such as polyvinyl chloride, polyester, nylon, and polyurethane, or laminates, porous films, foams, woven fabrics, non-woven fabrics, or paper materials.

In the transdermal absorption patch preparation of the present invention, if the release liner used is a substance generally used as a patch, there is no particular limitation. As specific examples of the release liner, preferably, polyethylene terephthalate, polypropylene, paper, and the like can be cited. More preferably, polyethylene terephthalate can be cited. In order to make the release liner have the most suitable release force, it can be treated with silicon dioxide as needed.

The transdermal absorption patch preparation of the present invention can be produced, for example, in the following manner.

Zonisamide or its alkali metal salt, percutaneous absorption enhancer and adhesive (other ingredients can be added as needed) are dissolved in an appropriate solvent to obtain an adhesive solution. The above-mentioned solvent can be appropriately selected according to the types of constituent components. For example, toluene, ethyl acetate, N-methyl-2-pyrrolidone, ethanol, methanol, etc., can be used singly or as a mixture of two or more kinds. Next, the adhesive solution thus obtained is spread on a release liner or support, and after the solvent is dried and removed, it is attached to the support or the release liner to obtain the transdermal absorption patch preparation of the present invention .

The thickness of the adhesive layer (a layer containing zonisamide or its alkali metal salt, a transdermal absorption enhancer, an adhesive, and other additives as necessary) is preferably 30 μm to 200 μm. More preferably, 50 μm to 200 μm can be cited. More preferably, 50 μm to 150 μm can be cited.

If the thickness of the adhesive layer is less than 30 μm, the durability of drug release is reduced. It is preferably 30 μm or more, more preferably 50 μm or more. on the other hand, When the thickness of the above-mentioned adhesive layer exceeds 200 μm, the content of the drug in the adhesive layer increases, which increases the amount of remaining drug, resulting in an increase in manufacturing cost. It is preferably 200 μm or less, more preferably 150 μm or less.

This application claims the priority of the Japanese Patent Application No. 2016-062531 filed on March 25, 2016. All the contents of the specification of Japanese Patent Application No. 2016-062531 filed on March 25, 2016 can be cited by the present invention.

[Examples]

Hereinafter, examples are listed to specifically describe the present invention, but the present invention is not limited to the following examples. In addition, unless otherwise specified, "%" means "% by mass" when the total amount of the adhesive layer is 100% by mass.

Analysis 1-1: Analysis of various absorption enhancers

Using zonisamide as zonisamide or its alkali metal salt, the following experiment was performed.

Example 1

4 g of zonisamide and 7.5 g of N-lauryl pyrrolidone (N-lauryl-2-pyrrolidone) were dissolved in 20 mL of N-methyl-2-pyrrolidone to prepare a main drug solution. Mix the main drug solution with 295g ethyl acetate solution in which 88.5g of (meth)acrylic copolymer containing pyrrolidone group (2-ethylhexyl acrylate‧vinylpyrrolidone) is dissolved, and then add ethyl acetate to make the total It is 400 g, and after stirring and mixing until uniform, an adhesive solution is obtained. Next, spread the adhesive solution appropriately on a release liner (PET film), and then dry to remove N-methyl-2-pyrrolidone and ethyl acetate to form an adhesive with a thickness of 50μm Agent layer. Next, by bonding to a support (PET film), Example 1 was obtained. Each The content of the components is shown in Table 1. In addition, a blank field in Table 1 means that it has not been added.

Comparative example 1

Except not using N-laurylpyrrolidone and setting the content of the pyrrolidone group-containing (meth)acrylic copolymer to be the content shown in Table 1, Comparative Example 1 was obtained using the same method as Example 1. The content of each component is shown in Table 1.

Comparative example 2~4

Except that the transdermal absorption enhancer shown in Table 1 was used instead of N-laurylpyrrolidone, the same method as in Example 1 was used to obtain Comparative Examples 2 to 4. The content of each component is shown in Table 1.

Comparative example 5~13

Except that the transdermal absorption enhancer shown in Table 1 is used instead of N-laurylpyrrolidone, and the content of the (meth)acrylic copolymer containing pyrrolidone group and the transdermal absorption enhancer is the content shown in Table 1 , Using the same method as in Example 1 to obtain Comparative Examples 5-13. The content of each component is shown in Table 1.

Example 2

Except that the content of the pyrrolidone group-containing (meth)acrylic copolymer and the above-mentioned N-laurylpyrrolidone was set to the content shown in Table 2, the same method as in Example 1 was used to obtain Example 2. The content of each component is shown in Table 2. In addition, the blank column in Table 2 means that it has not been added.

Comparative examples 14-19

Except that the transdermal absorption enhancer shown in Table 2 is used instead of the above-mentioned N-laurylpyrrolidone, and the content of the above-mentioned (meth)acrylic copolymer containing pyrrolidone group and the transdermal absorption enhancer is as shown in Table 2 Except for the content, the same method as in Example 1 was used to obtain Comparative Examples 14-19. The content of each component is shown in Table 2 Show.

The skin penetration test of zonisamide in hairless rats in vitro

In order to analyze the transdermal absorbability of zonisamide in the transdermal absorption patch preparation of the present invention, the preparations of Examples 1, 2 and Comparative Examples 1 to 19 were subjected to in vitro skin penetration in hairless rats. experiment. The skin taken from the abdomen of a male hairless rat (HWY strain, 7 weeks old) was placed in a Franz-type diffusion tank, and each of the above-mentioned test preparations cut into a circle (ψ 14 mm) was attached. Fill one side of the receiver with phosphate buffered saline, and reflux 37°C warm water in a water jacket. As time passed, the liquid in the receiver was sampled, and the content of zonisamide penetrating the skin was determined by liquid chromatography, and the cumulative drug penetrating amount 24 hours after the start of the test was calculated. The conditions of liquid chromatography are as follows.

[HPLC measurement conditions]

Column: ACQUITY BEH C18 column (particle size 1.7μm, inner diameter x length; 2.1 x100mm)

Flow rate: 0.4mL/min

Column temperature: 30℃

Wavelength: 285nm

Mobile phase: methanol/water/acetic acid=18:82:1

The test results are shown in Table 1 and 2

From Tables 1 and 2, the following analysis can be performed.

Example 1 in Table 1 is an example that satisfies the constitutional requirements of the present invention, and Comparative Examples 1 to 13 are examples where the transdermal absorption enhancer (N-alkylpyrrolidone) specified in the present invention is not used, or other transdermal absorption enhancers are used example of. Compared with Comparative Examples 1-13, the cumulative drug penetration of Example 1 is greatly increased, showing excellent transdermal absorbability.

Among them, the content of the percutaneous absorption enhancer of Comparative Examples 5 to 13 is 10% by mass, which is an example in which the content of the percutaneous absorption enhancer is higher than that of Example 1 (7.5% by mass). Even though the content of the percutaneous absorption enhancer of Example 1 is less than that of Comparative Examples 5-13, it still shows transdermal absorbability that is about 1.2 to 4 times that of Comparative Examples 5-13.

Example 2 in Table 2 is an example that satisfies the constitutional requirements of the present invention. Comparative Examples 14 to 19 are examples where the transdermal absorption enhancer (N-alkylpyrrolidone) specified in the present invention is not used, but other transdermal absorption enhancers are used. . Example 2 shows that the transdermal absorbability is about 1.7 to 4.8 times that of Comparative Examples 14 to 19 using other transdermal absorption enhancers.

It can be seen from the above that in the present invention, it is not sufficient to use only the (meth)acrylic copolymer containing pyrrolidone group as an adhesive, and N-laurylpyrrolidone (N-alkylpyrrolidone) is used as a transdermal absorption enhancer. ) Is very important for improving transdermal absorbability.

Analysis 1-2: Analysis of the combination of N-laurylpyrrolidone and other absorption enhancers, and the combination of (meth)acrylic copolymers containing pyrrolidone groups and (meth)acrylic copolymers containing carboxyl groups

Examples 3~7

In addition to using the transdermal absorption enhancers described in Table 3 and containing pyrrolidine Except that the content of the ketone-based (meth)acrylic copolymer and the transdermal absorption accelerator is the content shown in Table 3, the same method as in Example 1 was used to obtain Examples 3 to 7. The content of each component is shown in Table 3. In addition, the blank column in Table 3 means that it has not been added.

Comparative example 20

Except that the transdermal absorption enhancer described in Table 3 is used instead of N-laurylpyrrolidone, and the content of the (meth)acrylic copolymer containing pyrrolidone group and the transdermal absorption enhancer is the content shown in Table 3. Using the same method as in Example 1, Example 20 was obtained. The content of each component is shown in Table 3.

Examples 8~11

Except that the transdermal absorption enhancer described in Table 4 was used, and the contents of zonisamide, pyrrolidone group-containing (meth)acrylic copolymer, and transdermal absorption enhancer were set to the contents shown in Table 4, use In the same manner as in Example 1, Examples 8 to 11 were obtained. The content of each component is shown in Table 4. The blank column in Table 4 means that it has not been added.

Example 12

Except for the use of (meth)acrylic copolymers containing carboxyl groups (acrylic acid‧octyl acrylate copolymers), and the contents of zonisamide, acrylic copolymers, and transdermal absorption enhancers are as shown in Table 4 Otherwise, the same method as in Example 1 was used to obtain Example 12. The content of each component is shown in Table 4.

Examples 13~21

Except that the transdermal absorption enhancer described in Table 4 was used, and the content of the acrylic copolymer and the transdermal absorption enhancer were as shown in Table 4, the same method as in Example 12 was used to obtain Example 13 ~21. The content of each ingredient As shown in Table 4.

Comparative Example 21

Except that the transdermal absorption enhancer described in Table 4 was used instead of N-laurylpyrrolidone, and the content of zonisamide, pyrrolidone group-containing (meth)acrylic copolymer, and transdermal absorption enhancer were in Table 4 Except for the content shown, the same method as in Example 1 was used to obtain Example 21. The content of each component is shown in Table 4.

The skin penetration test of zonisamide in hairless rats in vitro

For the preparations of Examples 3 to 21 and Comparative Examples 20 and 21, the same method as the above-mentioned in vitro hairless rat skin penetration experiment was used to perform the outer skin penetration experiment on the hairless rat. The results are shown in Tables 3 and 4.

From Tables 3 and 4, the following analysis can be performed.

Examples 3 to 7 in Table 3 are examples of using the percutaneous absorption enhancer (N-alkylpyrrolidone) specified in the present invention and other percutaneous absorption enhancers that satisfy the constitutional requirements of the present invention. In addition, Comparative Example 20 in Table 3 is an example in which the percutaneous absorption enhancer specified in the present invention is not used, but two other percutaneous absorption enhancers are used. Compared with Comparative Example 20, the cumulative drug penetration of Examples 3-7 increased, showing excellent transdermal absorbability. Among them, Example 4 using isopropyl myristate as another transdermal absorption enhancer had the highest cumulative drug penetration.

From the foregoing, it is understood that the use of N-laurylpyrrolidone and other transdermal absorption enhancers in the present invention is also effective. In particular, the combination of N-laurylpyrrolidone and isopropyl myristate can effectively improve transdermal absorbability.

Examples 8 to 11 in Table 4 are examples of using the transdermal absorption enhancer (N-alkylpyrrolidone) specified in the present invention, and one or two other percutaneous absorption enhancers that satisfy the constitutional requirements of the present invention. In addition, Comparative Example 21 in Table 4 did not use the percutaneous absorption enhancer specified in the present invention, but used two other percutaneous absorption enhancers. Compared with Comparative Example 21, the cumulative drug penetration of Examples 8 to 11 increased, showing excellent transdermal absorbability.

Example 12 of Table 4 is the use of (meth)acrylic copolymers containing pyrrolidone groups and (meth)acrylic copolymers containing carboxyl groups as adhesives, and the transdermal absorption enhancer (N -Alkylpyrrolidone) which satisfies the requirements of the present invention. Compared with Comparative Example 21, the cumulative drug penetration of Example 12 was increased, showing excellent transdermal absorbability.

Examples 13 to 21 in Table 4 use (meth)acrylic copolymers containing pyrrolidone groups and (meth)propylene containing carboxyl groups as adhesives For the acid copolymer, one or two types of the percutaneous absorption enhancer (N-alkylpyrrolidone) specified in the present invention and other percutaneous absorption enhancers satisfying the constitutional requirements of the present invention are used. Compared with Comparative Example 21, the cumulative drug penetration of Examples 13 to 21 increased, showing excellent transdermal absorbability.

Comparing Example 11 and Example 17 in Table 4, Example 17 containing a carboxyl-containing (meth)acrylic copolymer has a higher cumulative drug penetration than Example 11, showing excellent performance Skin absorbability.

It can be seen from the above that in the present invention, in addition to the (meth)acrylic copolymer containing a pyrrolidone group as an adhesive, the use of a (meth)acrylic copolymer containing a carboxyl group can also effectively improve the transdermal absorbability.

Analysis 2: Analysis of skin irritation

Comparative example 22

Except that the transdermal absorption enhancer described in Table 5 is used instead of N-laurylpyrrolidone, and the content of the carboxyl group-containing (meth)acrylic copolymer and the transdermal absorption enhancer is the content shown in Table 5, use In the same manner as in Example 1, Comparative Example 22 was obtained. The content of each component is shown in Table 5. In addition, the blank column in Table 5 means that it has not been added.

Rabbit skin irritation test

The rabbit skin irritation test was performed on the preparations of Examples 2, 11 and 17, and Comparative Examples 1 and 22. Attach each patch to the back of the depilated rabbit for 24 hours. According to the following Draize method, add the average of the erythema and edema scores after 1 hour, 2 hours, and 48 hours after peeling to obtain a skin irritation. Index (Primary Irritation Index: PII). P.I.I. values are shown in Table 5. In addition, the safety evaluation benchmarks are shown in Table 6. Furthermore, regarding the P.I.I. value of Example 11 due to peeling The post-residual glue is therefore used as a reference value.

(Evaluation criteria and scoring)

Formation of erythema and crust

No erythema: 0

Very mild erythema (barely recognizable): 1

Clear erythema: 2

Moderate to high degree erythema: 3

Formation of high erythema to mild crust (deep injury): 4

Formation of puffiness

No edema: 0

Very mild edema (barely recognizable): 1

Mild edema (clear uplift, able to clearly identify the edge): 2

Moderate edema (about 1mm swelling): 3

High edema (a bulge above 1mm and the width exceeding the exposure range): 4

Examples 2, 11, and 17 in Table 5 are examples that satisfy the constituent requirements of the present invention. Comparative Example 22 in Table 5 is an example in which polycinnamyl alcohol (BL-4.2) is used in place of the transdermal absorption enhancer specified in the present invention (the above-mentioned N-laurylpyrrolidone). Compared with the irritation index of Comparative Example 22 containing polycinnamyl alcohol (BL-4.2), the irritation index is 5.8. Although the content of the percutaneous absorption enhancer in Examples 2 and 11 of the present invention is the same as or higher than that of Comparative Example 22, the irritation index is respectively It is about 2.0, with high safety.

In addition, the irritation index of Example 17 containing the above-mentioned (meth)acrylic adhesive containing carboxyl groups was 0.9, which was extremely safe. As shown in Table 4, the transdermal absorption promotion of Example 17 is better than that of Example 11. By including a carboxyl-containing (meth)acrylic adhesive, it can improve transdermal absorbability and reduce skin irritation. Sex.

Compared with the irritation index of Comparative Example 1 which does not contain a transdermal absorption enhancer, the irritation index is 1.5, and the irritation index of Example 17 is 0.9. The preparation of percutaneous absorption enhancer has high safety.

Claims (17)

A transdermal absorption patch preparation comprising an adhesive layer containing the following ingredients: zonisamide or its alkali metal salt; an adhesive containing a (meth)acrylic copolymer having a pyrrolidone group, and an adhesive layer containing N- The percutaneous absorption enhancer of alkylpyrrolidone, wherein the N-alkylpyrrolidone is N-laurylpyrrolidone, N-octylpyrrolidone, N-heptylpyrrolidone, N-hexylpyrrolidone, N-nonylpyrrolidone, N-decyl Pyrrolidone, N-undecylpyrrolidone, N-tridecylpyrrolidone, N-tetradecylpyrrolidone, N-pentadecylpyrrolidone, N-hexadecylpyrrolidone, N-heptadecylpyrrolidone Or N-octadecylpyrrolidone. According to the percutaneous absorption patch preparation described in item 1 of the scope of patent application, the N-alkylpyrrolidone is N-laurylpyrrolidone or N-octylpyrrolidone. According to the percutaneous absorption patch preparation described in item 2 of the scope of patent application, the N-alkylpyrrolidone is N-laurylpyrrolidone. The percutaneously absorbable patch preparation described in item 1 or 2 of the scope of the patent application, wherein the adhesive is a (meth)acrylic copolymer having a pyrrolidone group and a (meth)acrylic copolymer having a carboxyl group . According to the percutaneous absorption type patch preparation described in item 1 or 2 of the scope of patent application, wherein the percutaneous absorption enhancer comprises N-laurylpyrrolidone, and selected from polyethylene glycol monolaurate, lauric alcohol, Isopropyl myristate, palm At least one of the group consisting of isopropyl acid, oleyl oleate, and hexyl laurate. The transdermal absorption type patch preparation described in claim 5, wherein the percutaneous absorption enhancer comprises N-laurylpyrrolidone and isopropyl myristate. According to the percutaneous absorption patch preparation described in item 1 or 2 of the scope of patent application, the (meth)acrylic copolymer having a pyrrolidone group is acrylic acid 2-ethylhexyl‧vinylpyrrolidone copolymer, acrylic acid hydroxy Ethyl ethyl ‧ vinyl pyrrolidone copolymer, butyl acrylate ‧ vinyl pyrrolidone copolymer, cyclohexyl acrylate‧ vinyl pyrrolidone copolymer, 2-ethylhexyl methacrylate‧ vinyl pyrrolidone copolymer, cyclohexyl methacrylate‧ Vinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧methylvinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧hydroxyethyl acrylate‧vinylpyrrolidone copolymer, 2-ethylhexyl acrylate‧acrylic acid‧vinyl Pyrrolidone copolymer, butyl acrylate‧acrylic acid‧vinylpyrrolidone copolymer, or 2-ethylhexyl acrylate‧acrylic acid‧methyl vinylpyrrolidone copolymer. According to the percutaneous absorption patch preparation described in item 7 of the scope of patent application, the (meth)acrylic copolymer having a pyrrolidone group is 2-ethylhexyl acrylate·vinylpyrrolidone copolymer. The transdermal absorption patch preparation described in item 4 of the scope of patent application, wherein the (meth)acrylic copolymer with carboxyl group is acrylic acid‧octyl acrylate copolymer, 2-ethylhexyl acrylate‧vinyl acetate ‧Acrylic acid copolymer, 2-ethylhexyl acrylate‧Methyl acrylate‧Acrylic acid‧Methacrylic acid Glycidyl ester copolymer, acrylic acid‧butyl acrylate copolymer, acrylic acid‧hydroxyethyl acrylate copolymer, or 2-ethylhexyl acrylate‧vinyl acetate‧butyl acrylate‧acrylic acid copolymer. According to the percutaneous absorption patch preparation described in item 9 of the scope of patent application, the (meth)acrylic copolymer with carboxyl group is acrylic acid‧octyl acrylate copolymer. According to the percutaneous absorption type patch preparation described in item 1 or 2 of the scope of patent application, the content of the zonisamide or its alkali metal salt in the percutaneous absorption type patch preparation is based on zonisamide In conversion, it is 1% by mass to 20% by mass relative to the total amount of the adhesive layer. According to the percutaneous absorption type patch preparation described in item 1 or 2 of the scope of patent application, the content of the adhesive in the percutaneous absorption type patch preparation is 30 mass relative to the total amount of the adhesive layer %~98% by mass. The transdermal absorption type patch preparation described in item 1 or 2 of the scope of patent application, wherein the content of the transdermal absorption enhancer in the transdermal absorption type patch preparation is relative to the total amount of the adhesive layer It is 1% by mass to 40% by mass. The transdermal absorption type patch preparation described in item 1 or 2 of the scope of patent application, wherein the compounding amount of the adhesive in the transdermal absorption type patch preparation is relative to the zonisamide or its alkali metal Salt 1 quality department, 1.5 quality department ~ 40 quality department. The percutaneous absorption type patch preparation described in item 1 or 2 of the scope of patent application, wherein the compounding amount of the transdermal absorption enhancer in the percutaneous absorption type patch preparation is relative to the zonisamide or The alkali metal salt has 1 part by mass and is 0.05 to 40 parts by mass. The transdermal absorption patch preparation described in item 1 of the scope of patent application, wherein the adhesive comprises 2-ethylhexyl acrylate‧vinylpyrrolidone copolymer and acrylic acid‧octyl acrylate copolymer, the percutaneous absorption enhancer Containing N-laurylpyrrolidone and isopropyl myristate, the blending amount of the adhesive is 10 parts by mass to 25 parts by mass relative to 1 part by mass of the zonisamide or its alkali metal salt, and the transdermal absorption is promoted The compounding amount of the agent is 1 part by mass to 10 parts by mass. According to the percutaneous absorption type adhesive preparation described in item 1 or 2 of the scope of patent application, the thickness of the adhesive layer is 30 μm to 200 μm.